University of Chicago Autoimmunity Center of Excellence

描述(由申请人提供)：芝加哥大学自身免疫卓越中心(UCACE)的中心主题是自身免疫性疾病的耐受性和适应性免疫。UCACE有两个压倒一切的目标。第一个是确定适应性自身免疫如何在具有特定终末器官受累的自身免疫性疾病中原位进化和传播。我们将集中讨论狼疮性肾炎(LN)，这是系统性红斑狼疮(SLE)最常见的严重表现。进展为肾功能衰竭与肾小管间质炎症(TII)相关，与TII相关的免疫过程是肾脏固有的。这些过程没有完全反映在外周血中，SLE小鼠模型不能模拟人类狼疮TII的原位获得性免疫反应。因此，动物模型不能替代人类的主要研究。在ACE的最后一个周期中，我们开发了新的方法来研究人体组织的原位免疫。我们现在可以克隆原位表达的抗体，表达这些抗体，并鉴定它们结合的抗原。然而，识别原位识别的抗原并不足以理解这些B细胞是如何被原位选择的。正如在合作和试点项目中所描述的，我们已经开发了新的计算工具来识别人类炎症中的同源细胞：细胞相互作用和细胞组织的全球模式。在合作项目中，我们将把这些研究扩展到其他疾病状态，以建立原位耐受在自身免疫中失败的特定和全球机制。 UCACE将追求的第二个目标是对第一个目标的补充。第一篇论述了自身免疫是如何在原位传播的，第二篇研究了丧失耐受性和自身免疫在对感染的保护性免疫发展过程中的后果。令人惊讶的是，SLE患者对流感疫苗接种后产生的体液免疫反应比正常对照组更有效。在初级项目中，我们将确定增强的保护性免疫力是否是与SLE相关的更广泛的免疫球蛋白谱系的结果，以及/或者SLE的细胞因子环境是否能够提供更好的保护性免疫力。 相关性：芝加哥大学自身免疫学的重点是狼疮。狼疮是一种严重的全身自身免疫性疾病，后果严重，我们几乎没有有效的治疗方法。此外，这些治疗方法中的许多都具有很强的毒性。UCACE的目标之一是更好地了解狼疮，这将使开发更有效和毒性更低的治疗方法成为可能。 主要项目：探索SLE患者外周血B细胞选择改变的机制基础 项目负责人(PL)：威尔逊、帕特里克·C 描述(由申请人提供)：在UChicago ACE前一个资助期的令人惊讶的发现中，我们发现系统性红斑狼疮(SLE)患者产生了更高亲和力和更强的中和抗流感抗体(手稿正在准备中)。我们还在SLE的MRL-LPR/LPR小鼠模型中证明了这一趋势。这些发现提出了两个主要假说之一，我们认为这两个假说对理解SLE的病因至关重要。首先，一般情况下，制造高亲和力抗体的人患狼疮的风险也很高。所有人都可能时不时地做出自身抗体反应。然而，在任何免疫反应中容易产生高亲和力抗体的个体都可能产生高亲和力，因此病理性自身抗体在某些情况下会随着表位的扩散而导致SLE。第二种可能性是，自身免疫可能会改善抗体反应。因此，高亲和力和伴随的自身免疫被选在一起，增加了系统性红斑狼疮的风险。这就是自身免疫谱，或与自身免疫相关的其他特征，如炎症，能够实现更有效的抗体反应。在这一新的应用中，我们建议测试各种假设，以揭示SLE患者对流感和其他疫苗产生更有效的体液免疫反应的机制。我们还注意到，与对照受试者的抗体不同，SLE患者的抗体对自身抗原有独特的反应，而不是多反应的。这些发现表明，在SLE患者中，在外周免疫反应过程中针对多反应的选择是完整的，支持狼疮病理模型，在该模型中，在自身抗原特异性反应中产生高亲和力自身抗体。在具体目标1中，我们将进行实验来探索这一假说。在特定的目标2和3中，我们将探索在SLE患者和对照组(目标2)或在自身免疫的小鼠模型(目标3)中产生高亲和力的机制基础，反之，在SLE患者和对照组(目标2)或在自身免疫的小鼠模型(目标3)中产生易于自身免疫的反应。这些实验将为为什么在普通人群中保持自身免疫力提供洞察力。 相关性：我们发现狼疮患者在接种疫苗后对流感产生更高的亲和力抗体。这一发现表明，SLE可能是由于允许对病原体产生更高亲和力的抗体反应的选择性优势所致。了解患者产生更高亲和力和自身反应性抗体的机制对于了解SLE的潜在原因很重要。

DESCRIPTION (provided by applicant): The central theme of the University of Chicago Autoimmune Center of Excellence (UCACE) is tolerance and adaptive immunity in autoimmune diseases. The UCACE has two over-riding goals. The first is to determine how adaptive autoimmunity evolves and is propagated in situ in autoimmune diseases with specific end organ involvement. We will focus on lupus nephritis (LuN) which is the most common severe manifestation of systemic lupus erythematosus (SLE). Progression to renal failure correlates with tubulointerstitial inflammation (TII) and that the immunological processes associated with TII are intrinsic to the kidney. These processes are not fully reflected in the peripheral blood an murine models of SLE do not mimic the in situ adaptive immune responses of human lupus TII. Therefore, animal models cannot substitute for primary studies in humans. During the last cycle of the ACE, we developed novel methods to study in situ immunity in human tissue. We can now clone in situ expressed antibodies, express these antibodies and characterize the antigens they bind. However, identifying the antigens recognized in situ is not sufficient to understand how those B cells are being selected in situ. As described in the Collaborative and Pilot Projects, we have developed novel computational tools to identify both cognate cell:cell interactions and global patterns of cellular organization in human inflammation. In the Collaborative Project, we will extend these studies to other disease states to establish specific and global mechanisms by which in situ tolerance fails in autoimmunity. The second goal to be pursued by the UCACE is complementary to the first. While the first addresses how autoimmunity is propagated in situ, the second examines the consequences of a loss of tolerance, and autoimmunity, in the development of protective immunity to infection. Surprisingly, SLE patients mount more effective humoral immune responses to influenza vaccination than normal controls. In the Primary Project, we will determine if enhanced protective immunity is a consequence of the broader immunoglobulin repertoire associated with SLE and/or if the cytokine milieu of SLE enables better protective immunity. RELEVANCE: The focus of the University of Chicago Autoimmunity is on lupus. Lupus is a severe body-wide autoimmune disease with severe consequences and for which we have few effective therapies. Furthermore, many of these treatments are very toxic. One goal of the UCACE is to better understand lupus which will enable the development of more effective and less toxic therapies. Principal Project: Exploring the mechanistic basis for altered peripheral B cell selection in SLE Project Leader (PL): Wilson, Patrick C. DESCRIPTION (as provided by applicant): In surprising findings from the previous funding period of the UChicago ACE we found that systemic lupus erythematous (SLE) patients generated higher-affinity and more potently neutralizing anti-influenza antibodies (manuscript in preparation). We have also demonstrated this tendency in the Mrl-lpr/lpr mouse model of SLE. These findings suggest one of two primary hypotheses that we believe are of central importance to understanding the cause of SLE. First, there is the possibility that people who make higher affinity antibodies in general are also at a higher risk for lupus. All people likely make autoantibody responses from time to time. However, individuals that are prone to make high affinity antibodies during any immune response may make higher affinity and therefore pathological autoantibodies on occasion that with epitope spreading will result in SLE. The second possibility is that autoimmunity may improve antibody responses. Thus higher-affinity and concomitantly autoimmunity are selected together, increasing the risk for SLE. That is the autoimmune repertoire, or other features associated with autoimmunity such as inflammation, enables more effective antibody responses. In this renewal application, we propose to test various hypotheses to reveal the mechanisms by which SLE patients mount more effective humoral immune responses to influenza and other vaccines. We also noted that unlike control subject antibodies that were somewhat autoreactive, those from SLE patients were uniquely reactive to self-antigens without being polyreactive. These findings suggest that in SLE patients, selection against polyreactivity during peripheral immune responses is intact, supporting a model for lupus pathology in which high-affinity autoantibodies are generated in self-antigen specific responses. In Specific Aim 1 we will perform experiments to explore this hypothesis. In Specific Aims 2 and 3 we will explore the mechanistic basis for generating high affinity, and conversely, autoimmune-prone responses in SLE patients and controls (Aim 2) or in mouse models of autoimmunity (Aim 3). These experiments will provide insight into why autoimmunity might be maintained in the general population. RELEVANCE: We have found that lupus patients make higher affinity antibodies to influenza upon vaccination. This finding suggests that SLE may have resulted from a selective advantage allowing higher affinity antibody responses to pathogens. Understanding the mechanism by which higher affinity and self-reactive antibodies are produced by patients is important for understanding the underlying causes of SLE.